After graduation he worked in property and economic development, rising to become director of a £3 million practice. From 1983 to 1985, he worked as a graduate surveyor for Knight Frank, then as development surveyor for Derrick Wade & Waters where he became manager of the London office from 1985 to 1989. He was a marketing director from 1989–91, then principal of the Mark Prisk Connection from 1991 to 1997. From 1997 to 2001, he was company owner of MP2.

He was a former Chairman of Cornwall Young Conservatives and after two unsuccessful parliamentary battles in 1992 (Newham North West) and 1997 (Wansdyke), he was finally elected as the Conservative MP for the constituency of Hertford and Stortford in 2001. He has been promoted from the backbenches to serve at various points as Shadow Financial Secretary, Shadow Minister for Economic Affairs, an opposition whip and Shadow Minister for Business and Enterprise. He is author of several pamphlets on urban design.

On 26 July 2007, David Cameron then Prime Minister appointed Mark Prisk as Shadow Minister for Cornwall, although there is no government post of Minister for Cornwall for the opposition to formally shadow. The party said that the move was intended to help place the county's concerns "at the heart of Conservative thinking". Conservative Party leader David Cameron said he wholeheartedly endorsed the appointment and it would ensure that the voice of Cornwall was heard.[4] The post was discontinued following the 2010 general election, and currently there is no "minister for Cornwall".

Liberal DemocratMPMatthew Taylor accused the Conservative Party of using the appointment in a bid to get around the rule that requires MPs to limit the local cases they take up to their own constituency, by claiming that party political activity by MPs outside their own constituencies was in the role of "Shadow Minister" for the areas concerned, despite there being no actual Minister to shadow.[5]

Mark Prisk defended his role as Shadow Minister for Cornwall in open letter to the Falmouth Packet dated Wednesday 28 November 2007. He noted that, "as a born and bred Cornishman", his role is to listen to the concerns of people in Cornwall, to feed these back to the Shadow Cabinet, and to make sure that Conservative policies properly reflect the needs of Cornwall.[6]

Prisk was appointed as the minister for Business and Enterprise in the Coalition government, until he was shifted to become the Housing minister on 5 September 2012.[8]

As minister for housing, Prisk was responsible for creating a "Future High Street Forum" to support struggling High Street retailers, but was asked to step down from the front benches in 2013, which he claimed was to make way for a younger generation.[9]